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The widespread use of high-resolution computed tomography in clinical and research settings has increased the detection of interstitial lung abnormalities (ILA) in asymptomatic and undiagnosed individuals. We reported that in smokers, ILA were present in about 1 of every 12 high-resolution computed tomographic scans; however, the long-term significance of these subclinical changes remains unclear. Studies in families affected with pulmonary fibrosis, smokers with chronic obstructive pulmonary disease, and patients with inflammatory lung disease have shown that asymptomatic and undiagnosed individuals with ILA have reductions in lung volume, functional limitations, increased pulmonary symptoms, histopathologic changes, and molecular profiles similar to those observed in patients with clinically significant interstitial lung disease (ILD). These findings suggest that, in select at-risk populations, ILA may represent early stages of pulmonary fibrosis or subclinical ILD. The growing interest surrounding this topic is motivated by our poor understanding of the inciting events and natural history of ILD, coupled with a lack of effective therapies. In this perspective, we outline past and current research focused on validating radiologic, physiological, and molecular methods to detect subclinical ILD. We discuss the limitations of the available cross-sectional studies and the need for future longitudinal studies to determine the prognostic and therapeutic implications of subclinical ILD in populations at risk of developing clinically significant ILD. [ABSTRACT FROM AUTHOR]

The use of simulation is gaining momentum in nurse education across the UK. The Nursing and Midwifery Council is currently investigating the use of simulation in pre-registration nursing. This article gives a brief history of simulation, discusses competence issues and why simulation is best placed to teach nurses in today's health service. An innovative approach to implementing simulation into the nursing curriculum is introduced. [ABSTRACT FROM AUTHOR]

Objectives: There have been limited investigations of the prevalence and mortality impact of quantitative CT (QCT) parenchymal lung features in RA. We examined the cross-sectional prevalence and mortality associations of QCT features, comparing RA and non-RA participants., Methods: We identified participants with and without RA in COPDGene, a multicentre cohort study of current or former smokers. Using a k-nearest neighbour quantifier, high resolution CT chest scans were scored for percentage of normal lung, interstitial changes and emphysema. We examined associations between QCT features and RA using multivariable linear regression. After dichotomizing participants at the 75th percentile for each QCT feature among non-RA participants, we investigated mortality associations by RA/non-RA status and quartile 4 vs quartiles 1-3 of QCT features using Cox regression. We assessed for statistical interactions between RA and QCT features., Results: We identified 82 RA cases and 8820 non-RA comparators. In multivariable linear regression, RA was associated with higher percentage of interstitial changes (β = 1.7 [0.5], P = 0.0008) but not emphysema (β = 1.3 [1.7], P = 0.44). Participants with RA and >75th percentile of emphysema had significantly higher mortality than non-RA participants (hazard ratio [HR] 5.86; 95% CI: 3.75, 9.13) as well as RA participants (HR 5.56; 95% CI: 2.71, 11.38) with ≤75th percentile of emphysema. There were statistical interactions between RA and emphysema for mortality (multiplicative P = 0.014; attributable proportion 0.53; 95% CI: 0.30, 0.70)., Conclusion: Using machine learning-derived QCT data in a cohort of smokers, RA was associated with higher percentage of interstitial changes. The combination of RA and emphysema conferred >5-fold higher mortality., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To explore the association between the extent of CT abnormalities by quantitative imaging analysis (QIA) and clinical/physiological disease parameters in patients with antisynthetase syndrome associated interstitial lung disease (ARS-ILD)., Methods: We analysed 20 patients with antisynthetase antibodies and active ILD enrolled in the Abatacept in Myositis-Associated Interstitial Lung Disease study. High-resolution chest CT was obtained at weeks 0, 24 and 48 and QIA scored the extent of ground glass (quantitative score for ground glass), fibrosis (quantitative score for lung fibrosis, QLF) and total ILD (quantitative ILD, QILD). Mixed-effects models estimated longitudinal QIA scores over time. Associations between QIA scores with clinical/physiological parameters were analysed longitudinally using repeated-measures mixed-effects models., Results: Patients were median age 57 years, 55% males and 85% white. Higher (worse) baseline QIA scores correlated with lower baseline forced vital capacity (FVC) and diffusing capacity adjusted for haemoglobin (DLCO). Longitudinal QIA trajectories trended towards improving scores during the trial, and patients on O 2 at baseline had worsening QIA trajectories which were different from patients who were not on O 2 . Longitudinal QIA scores demonstrated strong associations with both FVC and DLCO over time. Higher QILD scores over time were also associated with worse dyspnoea scores, pulmonary visual analogue scale, physician and patient global disease activity, health status in 6/8 domains of the Short Form-36 and higher oxygen requirements. Patients with significant radiographic improvement at 48 weeks had higher baseline QLF, QILD and worse DLCO., Conclusions: Longitudinal QIA scores associate with lung physiology, patient perception of respiratory status, overall disease activity and quality of life over time in ARS-ILD. QIA may allow reproducible monitoring of disease progression and response to therapy over time., Trial Registration Number: NCT03215927., Competing Interests: Competing interests: GK and JG are on the UCLA patent for the quantitative imaging analysis. RA has received research grants from Boehringer Ingelheim, Bristol Myers Squibb, EMD Serono, Janssen, Mallinckrodt, Pfizer and Q32, and serves as a consultant for Actigraph, Alexion, ANI Pharmaceuticals, Argenx, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Cabaletta Bio, Capella Bioscience, Corbus, CSL Behring, EMD Serono, Galapagos, Horizon Therapeutics, I-Cell, Janssen, Kezar, Kyverna, Merck, Novartis, Nuvig Therapeutics, Octapharma, Pfizer, Regeneron, Roivant, Sanofi, Teva, Artsome, Capstanx and Manta. CC-S has received research grants from Priovant, CSL Behring, Janssen, Octapharma, Pfizer, AbbVie and Bristol Myers Squibb, and serves as a consultant for Boehringer Ingelheim, Recludix, Octapharma, Pfizer, AbbVie and Bristol Myers Squibb. PFD is editor of UpToDate and a member of the FDA Advisory Committee. TJD has received support from Bayer and has been part of a clinical trial funded by Genentech, all unrelated to this study. GMH receives grant support from the NIH including R01 HL111024, R01 HL135142 and R01130974. He has performed consulting work for Boehringer Ingelheim and the Gerson Lehrman Group., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Anti-synthetase syndrome (ASSD) is a rare systemic autoimmune rheumatic disease (SARD) with significant heterogeneity and no shared classification criteria. We aimed to identify clinical and serological features associated with ASSD that may be suitable for inclusion in the data-driven classification criteria for ASSD., Methods: We used a large, international, multicenter "Classification Criteria for Anti-synthetase Syndrome" (CLASS) project database, which includes both patients with ASSD and controls with mimicking conditions, namely, SARDs and/or interstitial lung disease (ILD). The local diagnoses of ASSD and controls were confirmed by project team members. We employed univariable logistic regression and multivariable Ridge regression to evaluate clinical and serological features associated with an ASSD diagnosis in a randomly selected subset of the cohort., Results: Our analysis included 948 patients with ASSD and 1,077 controls. Joint, muscle, lung, skin, and cardiac involvement were more prevalent in patients with ASSD than in controls. Specific variables associated with ASSD included arthritis, diffuse myalgia, muscle weakness, muscle enzyme elevation, ILD, mechanic's hands, secondary pulmonary hypertension due to ILD, Raynaud phenomenon, and unexplained fever. In terms of serological variables, Jo-1 and non-Jo-1 anti-synthetase autoantibodies, antinuclear antibodies with cytoplasmic pattern, and anti-Ro52 autoantibodies were associated with ASSD. In contrast, isolated arthralgia, dysphagia, electromyography/magnetic resonance imaging/muscle biopsy findings suggestive of myopathy, inflammatory rashes, myocarditis, and pulmonary arterial hypertension did not differentiate between patients with ASSD and controls or were inversely associated with ASSD., Conclusion: We identified key clinical and serological variables associated with ASSD, which will help clinicians and offer insights into the development of data-driven classification criteria for ASSD., (© 2024 The Author(s). Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Objective: Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) includes multiple subtypes with varying histopathology, prognosis, and potential treatments. Limited research has investigated risk factors for different RA-ILD subtypes. Therefore, we examined demographic, serologic, and lifestyle associations with RA-ILD subtypes., Methods: We systematically identified RA-ILD cases and RA controls without ILD (RA-noILD) in the Brigham RA Sequential Study and Mass General Brigham Biobank RA cohort. We determined RA-ILD subtype (usual interstitial pneumonia [UIP], nonspecific interstitial pneumonia [NSIP], and other/indeterminate) through chest high-resolution computed tomography imaging pattern. We investigated associations of demographic, lifestyle, and serologic factors with major RA-ILD subtypes using multivariable logistic regression., Results: Among 3,328 patients with RA, we identified 208 RA-ILD cases and 547 RA-noILD controls. RA-UIP was associated with older age (odds ratio [OR] 1.03 per year, 95% confidence interval [95% CI] 1.01-1.05), male sex (OR 2.15, 95% CI 1.33-3.48), and seropositivity (OR 2.08, 95% CI 1.24-3.48), whereas RA-NSIP was significantly associated only with seropositive status (OR 3.21, 95% CI 1.36-7.56). Nonfibrotic ILDs were significantly associated with smoking (OR 2.81, 95% CI 1.52-5.21). Having three RA-ILD risk factors (male, seropositive, smoking) had an OR of 6.89 (95% CI 2.41-19.7) for RA-UIP compared with having no RA-ILD risk factors., Conclusion: Older age, seropositivity, and male sex were strongly associated with RA-UIP, whereas RA-related autoantibodies were associated with RA-NSIP. These findings suggest RA-ILD sex differences may be driven by RA-UIP and emphasize the importance of further studies to clarify RA-ILD heterogeneity and optimize screening and treatment approaches., (© 2024 American College of Rheumatology.)

Objective: We provide evidence-based recommendations regarding screening for interstitial lung disease (ILD) and the monitoring for ILD progression in people with systemic autoimmune rheumatic diseases (SARDs), specifically rheumatoid arthritis, systemic sclerosis, idiopathic inflammatory myopathies, mixed connective tissue disease, and Sjögren disease., Methods: We developed clinically relevant population, intervention, comparator, and outcomes questions related to screening and monitoring for ILD in patients with SARDs. A systematic literature review was performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A Voting Panel of interdisciplinary clinician experts and patients achieved consensus on the direction and strength of each recommendation., Results: Fifteen recommendations were developed. For screening people with these SARDs at risk for ILD, we conditionally recommend pulmonary function tests (PFTs) and high-resolution computed tomography of the chest (HRCT chest); conditionally recommend against screening with 6-minute walk test distance (6MWD), chest radiography, ambulatory desaturation testing, or bronchoscopy; and strongly recommend against screening with surgical lung biopsy. We conditionally recommend monitoring ILD with PFTs, HRCT chest, and ambulatory desaturation testing and conditionally recommend against monitoring with 6MWD, chest radiography, or bronchoscopy. We provide guidance on ILD risk factors and suggestions on frequency of testing to evaluate for the development of ILD in people with SARDs., Conclusion: This clinical practice guideline presents the first recommendations endorsed by the American College of Rheumatology and American College of Chest Physicians for the screening and monitoring of ILD in people with SARDs., (© 2024 American College of Rheumatology.)

Objective: We provide evidence-based recommendations regarding the treatment of interstitial lung disease (ILD) in adults with systemic autoimmune rheumatic diseases (SARDs)., Methods: We developed clinically relevant population, intervention, comparator, and outcomes questions. A systematic literature review was then performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A panel of clinicians and patients reached consensus on the direction and strength of the recommendations., Results: Thirty-five recommendations were generated (including two strong recommendations) for first-line SARD-ILD treatment, treatment of SARD-ILD progression despite first-line ILD therapy, and treatment of rapidly progressive ILD. The strong recommendations were against using glucocorticoids in systemic sclerosis-ILD as a first-line ILD therapy and after ILD progression. Otherwise, glucocorticoids are conditionally recommended for first-line ILD treatment in all other SARDs., Conclusion: This clinical practice guideline presents the first recommendations endorsed by the American College of Rheumatology and American College of Chest Physicians for the treatment of ILD in people with SARDs., (© 2024 American College of Rheumatology.)

We aimed to determine the prevalence and outcomes for forced vital capacity percent predicted (FVCpp) decline among patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). We identified patients with RA-ILD in the Mass General Brigham Healthcare system. RA-ILD diagnosis was determined by review of high-resolution computed tomography (HRCT) imaging by up to three thoracic radiologists. We abstracted FVCpp measurements, covariates, lung transplant, and ILD-related death from the medical record. We employed a relative FVCpp decline cutoff of > 10% within 24 months. We also used a group-based trajectory model to obtain patterns of change from RA-ILD diagnosis. We then assessed for associations of each FVC decline definition with risk of lung transplant or ILD-related death using multivariable logistic regression. We analyzed 172 patients with RA-ILD with a median of 6 FVCpp measurements per patient over 6.5 years of follow-up (mean age 62.2 years, 36% male). There were seven (4%) lung transplants and 44 (26%) ILD-related deaths. Ninety-eight (57%) patients had relative decline of FVCpp by > 10% in 24 months. We identified three trajectory groups of FVCpp change: rapidly declining (n = 24/168 [14%]), slowly declining (n = 90/168 [54%]), and stable/improving (n = 54/168 [32%]). The rapidly declining group and FVCpp > 10% had adjusted odds ratios (aOR) for lung transplant/ILD-related death of 19.2 (95%CI 4.9 to 75.5) and 2.8 (95%CI 1.3 to 6.1) respectively. Over half of patients with RA-ILD had declining FVCpp. The different trajectory patterns demonstrate the importance of FVC monitoring for identifying patients at the highest risk of poor outcomes. Key Points • Over half of patients with RA-ILD had declining FVCpp over a median of 6.5 years of follow-up. • The rapidly declining FVCpp trajectory group had stronger associations with lung transplant and ILD-related death compared to those with FVCpp decline by > 10%. • Clinicians can employ FVC monitoring to proactively treat patients who are at risk of poor outcomes., (© 2024. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Fibrotic interstitial lung diseases (fILDs) have poor survival rates and lack effective therapies. Despite evidence for immune mechanisms in lung fibrosis, immunotherapies have been unsuccessful for major types of fILD. Here, we review immunological mechanisms in lung fibrosis that have the potential to impact clinical practice. We first examine innate immunity, which is broadly involved across fILD subtypes. We illustrate how innate immunity in fILD involves a complex interplay of multiple cell subpopulations and molecular pathways. We then review the growing evidence for adaptive immunity in lung fibrosis to provoke a re-examination of its role in clinical fILD. We close with future directions to address key knowledge gaps in fILD pathobiology: (1) longitudinal studies emphasizing early-stage clinical disease, (2) immune mechanisms of acute exacerbations, and (3) next-generation immunophenotyping integrating spatial, genetic, and single-cell approaches. Advances in these areas are essential for the future of precision medicine and immunotherapy in fILD., Competing Interests: Declaration of interests In disclosures unrelated to this work: M.K. received research funding from GlaxoSmithKline. T.J.D. received research support from Bayer and Bristol Myers Squibb, consulting fees from Boehringer Ingelheim and L.E.K. consulting, and has been part of a clinical trial funded by Genentech, all unrelated to this study. L.K.D. received research grants from the Brazilian Ministry of Health (PROADI-SUS), Boehringer Ingelheim, and Bristol-Myers-Squibb. J.S.L. received grants from the NIH and Boehringer Ingelheim, an unrestricted research gift from Pliant, and consulting fees from Blade, Boehringer Ingelheim, United Therapeutics, Astra Zenca, and Eleven P15, all outside the submitted work. J.S.L. serves on the DSMB for UT, Avalyn and is an advisor for the Pulmonary Fibrosis Foundation, all outside the submitted work. L.K.D. received consulting fees from Boehringer Ingelheim, Roche, and Bristol-Myers-Squibb. J.A.S. has received research support from Bristol Myers Squibb and performed consultancy for AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers-Squibb, Gilead, Inova Diagnostics, Janssen, Optum, Pfizer, and ReCor unrelated to this work. C.M.H. serves in a scientific advisory role for the following companies: Lung Therapeutics, Lassen Therapeutics, Rubedo Life Sciences, and Structure Therapeutics. C.M.H. also consults for the Three Lakes Foundation. C.M.H. receives research funding from Kyowa Kirin Co, Ltd. B.B.M. is a grant review consultant for Boehringer-Ingelheim, the Pulmonary Fibrosis Foundation and the National Scleroderma Foundation. W.M.O. has received consulting fees from Nikang Therapeutics on a topic unrelated to the present manuscript. E.Y.K. receives research funding in fILD from Bayer AG, Roche Pharma Research and Early Development, and 10X Genomics. E.Y.K. has a PCT patent application (US2022/075673) concerning a method to treat fibrosis that is not mentioned in this manuscript. E.Y.K. has a financial interest in Novartis AG unrelated to this work. The funders had no role in the decision to publish or preparation of this manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard University, its affiliated academic health care centers, or the National Institutes of Health., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To compare longitudinal changes in spirometric measures between patients with rheumatoid arthritis (RA) and non-RA comparators., Methods: We analysed longitudinal data from two prospective cohorts: the UK Biobank and COPDGene. Spirometry was conducted at baseline and a second visit after 5-7 years. RA was identified based on self-report and disease-modifying antirheumatic drug use; non-RA comparators reported neither. The primary outcomes were annual changes in the per cent-predicted forced expiratory volume in 1 s (FEV 1 %) and per cent predicted forced vital capacity (FVC%). Statistical comparisons were performed using multivariable linear regression. The analysis was stratified based on baseline smoking status and the presence of obstructive pattern (FEV 1 /FVC <0.7)., Results: Among participants who underwent baseline and follow-up spirometry, we identified 233 patients with RA and 37 735 non-RA comparators. Among never-smoking participants without an obstructive pattern, RA was significantly associated with more FEV 1 % decline (β=-0.49, p=0.04). However, in ever smokers with ≥10 pack-years, those with RA exhibited significantly less FEV 1 % decline than non-RA comparators (β=0.50, p=0.02). This difference was more pronounced among those with an obstructive pattern at baseline (β=1.12, p=0.01). Results were similar for FEV 1 /FVC decline. No difference was observed in the annual FVC% change in RA versus non-RA., Conclusions: Smokers with RA, especially those with baseline obstructive spirometric patterns, experienced lower FEV 1 % and FEV 1 /FVC decline than non-RA comparators. Conversely, never smokers with RA had more FEV 1 % decline than non-RA comparators. Future studies should investigate potential treatments and the pathogenesis of obstructive lung diseases in smokers with RA., Competing Interests: Competing interests: PAJ reports grant funding and other support from Novartis, Galapagos and Boehringer Ingelheim, unrelated to this work. MM reports institutional grant support from Bayer and Honoraria from Chickasaw Nation. MHC has received grant funding from Bayer, unrelated to this work. TJD received support from Bayer and has been part of a clinical trial funded by Genentech, unrelated to this study. PFD reports grant funding from Bristol Myers Squibb. ZW has received grant funding from Bristol-Myers Squibb and Principia/Sanofi and consulting fees from Viela Bio, Zenas BioPharma, Horizon Therapeutics, Sanofi, MedPace, BioCryst, Amgen, Nkarta, Inc, Adicet Bio, and Therapeutic’s and participation in data safety monitoring board or advisory board for Sanofi, Horizon, Novartis, Visterra/Otsuka and Shionogi, unrelated to this work. GMH reports consulting fees from Boehringer-Ingelheim, and the Gerson Lehrman Group, unrelated to this work. EKS has received grant support from Bayer and Northpond Laboratories, unrelated to this work. SYA reports consulting fees from Verona Pharmaceuticals and Vertex Pharmaceuticals and is cofounder and co-owner of Quantitative Imaging Solutions. RSJE reports contracts from Lung Biotechnology and Insmed, received a grant support from Boehringer Ingelheim and is cofounder and an equity holder of Quantitative Imaging Solutions. GRW reports grants from Boehringer Ingelheim, consultancy for Pulmonx, Janssen Pharmaceuticals, Novartis, and Vertex, and is founder and co-owner of Quantitative Imaging Solutions. JS has received research support from Bristol Myers Squibb and performed consultancy for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, Pfizer, ReCor, Sobi, and UCB, unrelated to this work. Other authors report no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Recently, a genome-wide association study identified an association between RA-associated interstitial lung disease (ILD) and RPA3-UMAD1 rs12702634 in the Japanese population, especially for patients with a usual interstitial pneumonia (UIP) pattern. We aimed to replicate this association in a European population and test for interaction with MUC5B rs35705950., Methods: In this genetic case-control association study, patients with RA and ILD and controls with RA and no ILD were included from France, the USA and the Netherlands. Only cases and controls from European genetic ancestries determined by principal components analysis were included in the analyses. RA was defined by the 1987 ACR or 2010 ACR/EULAR criteria and ILD by chest high-resolution CT scan, except in the control dataset from the Netherlands, where the absence of ILD was determined by chart review. Patients were genotyped for RPA3-UMAD1 rs12702634 and MUC5B rs35705950. Associations were tested using logistic regression adjusted for sex, age at RA onset, age at ILD onset or at certified absence of ILD, tobacco smoking status and country of origin., Results: Among the 883 patients included, 322 were RA-ILD cases (36.5%). MUC5B rs35705950 was strongly associated with RA-ILD in all datasets {combined adjusted odds ratio [OR] 2.9 [95% CI 2.1, 3.9], P  = 1.1 × 10 -11 . No association between RPA3-UMAD1 rs12702634 and RA-ILD was observed [combined OR 1.2 (95% CI 0.8, 1.6), P  = 0.31. No interaction was found between RPA3-UMAD1 rs12702634 and MUC5B rs35705950 ( P  = 0.70)., Conclusion: Our findings did not support a contribution of RPA3-UMAD1 rs12702634 to the overall RA-ILD susceptibility in the European population., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

In 2022, concurrent outbreaks of hepatitis A, invasive meningococcal disease (IMD), and mpox were identified in Florida, USA, primarily among men who have sex with men. The hepatitis A outbreak (153 cases) was associated with hepatitis A virus genotype IA. The IMD outbreak (44 cases) was associated with Neisseria meningitidis serogroup C, sequence type 11, clonal complex 11. The mpox outbreak in Florida (2,845 cases) was part of a global epidemic. The hepatitis A and IMD outbreaks were concentrated in Central Florida and peaked during March--June, whereas mpox cases were more heavily concentrated in South Florida and had peak incidence in August. HIV infection was more common (52%) among mpox cases than among hepatitis A (21%) or IMD (34%) cases. Where feasible, vaccination against hepatitis A, meningococcal disease, and mpox should be encouraged among at-risk groups and offered along with program services that target those groups.

Introduction/rationale: Protein biomarkers may help enable the prediction of incident interstitial features on chest CT., Methods: We identified which protein biomarkers in a cohort of smokers (COPDGene) differed between those with and without objectively measured interstitial features at baseline using a univariate screen (t-test false discovery rate, FDR p<0.001), and which of those were associated with interstitial features longitudinally (multivariable mixed effects model FDR p<0.05). To predict incident interstitial features, we trained four random forest classifiers in a two-thirds random subset of COPDGene: (1) imaging and demographic information, (2) univariate screen biomarkers, (3) multivariable confirmation biomarkers and (4) multivariable confirmation biomarkers available in a separate testing cohort (Pittsburgh Lung Screening Study (PLuSS)). We evaluated classifier performance in the remaining one-third of COPDGene, and, for the final model, also in PLuSS., Results: In COPDGene, 1305 biomarkers were available and 20 differed between those with and without interstitial features at baseline. Of these, 11 were associated with feature progression over a mean of 5.5 years of follow-up, and of these 4 were available in PLuSS, (angiopoietin-2, matrix metalloproteinase 7, macrophage inflammatory protein 1 alpha) over a mean of 8.8 years of follow-up. The area under the curve (AUC) of classifiers using demographics and imaging features in COPDGene and PLuSS were 0.69 and 0.59, respectively. In COPDGene, the AUC of the univariate screen classifier was 0.78 and of the multivariable confirmation classifier was 0.76. The AUC of the final classifier in COPDGene was 0.75 and in PLuSS was 0.76. The outcome for all of the models was the development of incident interstitial features., Conclusions: Multiple novel and previously identified proteomic biomarkers are associated with interstitial features on chest CT and may enable the prediction of incident interstitial diseases such as idiopathic pulmonary fibrosis., Competing Interests: Competing interests: SA reports equity/dividends from Quantitative Imaging Solutions and consulting for Vertex Pharmaceuticals, Verona Pharmaceuticals and Triangulate Knowledge, all unrelated to the current work. TJD has received grant support from Bristol Myers Squibb, consulting fees from Boehringer Ingelheim and L.E.K. consulting, and has been part of a clinical trial funded by Genentech, unrelated to the current work. BC reports consulting fees from Quantitative Imaging Solutions, unrelated to the current work. RuSJE reports consulting fees from Quantitative Imaging Solutions, unrelated to the current work. VC reports no competing interests. NE reports no competing interests. RK reports grants and personal fees from AstraZeneca, personal fees from CVS Caremark, personal fees from Aptus Health, grants and personal fees from GlaxoSmithKline, personal fees from Boston Scientific, personal fees from Boston Consulting Group, all outside the submitted work. GL reports no competing interests. RB reports no competing interests. DOW reports advisory board membership and shareholder of Online Disruptive Technologies, unrelated to the current work. RaSJE reports equity/dividends from Quantitative Imaging Solutions, unrelated to the current work. IOR reports no competing interests. GRW reports grants from Boehringer Ingelheim, BTG Interventional Medicine and Janssen Pharmaceuticals; consultancies/advisory board participation for Boehringer Ingelheim, Janssen Pharmaceuticals, Pulmonx, Novartis, Philips, CSL Behring and Vertex; and equity/dividends from Quantitative Imaging Solutions, unrelated to the current work, all outside the submitted work. GRW’s wife works for Biogen., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: The CLASS (Classification Criteria of Anti-Synthetase Syndrome) project is a large international multicentre study that aims to create the first data-driven anti-synthetase syndrome (ASSD) classification criteria. Identifying anti-aminoacyl tRNA synthetase antibodies (anti-ARS) is crucial for diagnosis, and several commercial immunoassays are now available for this purpose. However, using these assays risks yielding false-positive or false-negative results, potentially leading to misdiagnosis. The established reference standard for detecting anti-ARS is immunoprecipitation (IP), typically employed in research rather than routine autoantibody testing. We gathered samples from participating centers and results from local anti-ARS testing. As an "ad-interim" study within the CLASS project, we aimed to assess how local immunoassays perform in real-world settings compared to our central definition of anti-ARS positivity., Methods: We collected 787 serum samples from participating centres for the CLASS project and their local anti-ARS test results. These samples underwent initial central testing using RNA-IP. Following this, the specificity of ARS was reconfirmed centrally through ELISA, line-blot assay (LIA), and, in cases of conflicting results, protein-IP. The sensitivity, specificity, positive likelihood ratio and positive and negative predictive values were evaluated. We also calculated the inter-rater agreement between central and local results using a weighted κ co-efficient., Results: Our analysis demonstrates that local, real-world detection of anti-Jo1 is reliable with high sensitivity and specificity with a very good level of agreement with our central definition of anti-Jo1 antibody positivity. However, the agreement between local immunoassay and central determination of anti-non-Jo1 antibodies varied, especially among results obtained using local LIA, ELISA and "other" methods., Conclusions: Our study evaluates the performance of real-world identification of anti-synthetase antibodies in a large cohort of multi-national patients with ASSD and controls. Our analysis reinforces the reliability of real-world anti-Jo1 detection methods. In contrast, challenges persist for anti-non-Jo1 identification, particularly anti-PL7 and rarer antibodies such as anti-OJ/KS. Clinicians should exercise caution when interpreting anti-synthetase antibodies, especially when commercial immunoassays test positive for non-anti-Jo1 antibodies.

Pulmonary fibrosis is recognized as occurring in association with a wide and increasing array of conditions, and it presents with a spectrum of chest CT appearances. Idiopathic pulmonary fibrosis (IPF), which corresponds histologically with usual interstitial pneumonia and represents the most common idiopathic interstitial pneumonia, is a chronic progressive fibrotic interstitial lung disease (ILD) of unknown cause. Progressive pulmonary fibrosis (PPF) describes the radiologic development of pulmonary fibrosis in patients with ILD of a known or unknown cause other than IPF. The recognition of PPF impacts management of patients with ILD-for example, in guiding initiation of antifibrotic therapy. Interstitial lung abnormalities are an incidental CT finding in patients without suspected ILD and may represent an early intervenable form of pulmonary fibrosis. Traction bronchiectasis and/or bronchiolectasis, when detected in the setting of chronic fibrosis, is generally considered evidence of irreversible disease, and progression predicts worsening mortality risk. Awareness of the association between pulmonary fibrosis and connective tissue diseases, particularly rheumatoid arthritis, is increasing. This review provides an update on the imaging of pulmonary fibrosis, with attention given to recent advances in disease understanding with relevance to radiologic practice. The essential role of a multidisciplinary approach to clinical and radiologic data is highlighted.

Objective: Our aim was to investigate the effectiveness and tolerability of antifibrotics in a real-world cohort of patients with rheumatoid arthritis-associated interstitial lung diseases (RA-ILD)., Methods: In this retrospective cohort study, we identified RA-ILD patients initiating antifibrotics at Mass General Brigham Integrated Health Care System, a large multi-hospital healthcare system in Boston, MA, USA. We used electronic query to identify all patients with at least 2 RA diagnosis codes and a prescription for either nintedanib or pirfenidone (2014-2023). All analyzed patients met 2010 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for RA and had definite RA-ILD according to Bongartz criteria. Data regarding pulmonary function test (PFT) results, adverse events (AEs), tolerability, and clinical data were collected. A linear mixed model with random intercept was used to compare the within-patient trajectory of the percent predicted forced vital capacity (FVCpp) within 18-months before to 18-months after antifibrotic initiation among those with these PFT data. Lung transplant-free survival and drug retention was estimated in a Kaplan-Meier analysis and a Cox regression analysis was performed to identify independent baseline factors associated with lung transplant or mortality., Results: We analyzed 74 patients with RA-ILD that initiated antifibrotics (mean age 67.8 years, 53 % male); 40 patients initiated nintedanib and 34 initiated pirfenidone. Median follow-up was 89 weeks (min 4, max 387). There was a significant improvement in the estimated slope of FVCpp after antifibrotic initiation (-0.3 % per year after initiation compared to -6.2 % per year before antifibrotic initiation, p = 0.03). Nintedanib and pirfenidone had similar FVCpp trajectory. Twenty-six patients (35 %) died and 4 (5 %) had undergone lung transplantation during follow-up. Male sex and heavy smoking were each associated with the composite outcome of lung transplant or mortality. AEs were reported in 41 (55 %) patients, with gastrointestinal (GI) AEs being most common (n = 30). The initial antifibrotic was discontinued in 34 (46 %) patients mostly due to GI AEs (n = 19). The median drug retention time was 142 weeks (95 %CI 56, 262) with no difference between nintedanib and pirfenidone (p = 0.68)., Conclusion: In this first real-world study of antifibrotic use dedicated to RA-ILD, antifibrotic initiation was associated with a modestly improved trajectory of FVCpp. AEs were frequently reported, particularly GI, and discontinuation was common. However, lung transplant and mortality rates were still high, emphasizing the need for further therapeutic strategies in patients with severe RA-ILD. These real-world data complement previous trial data that investigated efficacy and safety., Competing Interests: Declaration of Competing Interest Dr. Juge has received honoraria from Bristol Myers Squibb, Boehringer Ingelheim and AstraZeneca, and a grant from Novartis. Dr. Doyle has received support from Bayer and Bristol Myers Squibb, consulting fees from Boehringer Ingelheim and L.E.K. consulting, and has been part of a clinical trial funded by Genentech. Dr. Sparks has received research support from Bristol Myers Squibb and performed consultancy for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, and Pfizer, and ReCor unrelated to this work. Other authors report no financial disclosures., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Shortened telomere lengths (TLs) can be caused by single nucleotide polymorphisms and loss-of-function mutations in telomere-related genes (TRG), as well as ageing and lifestyle factors such as smoking. Our objective was to determine if shortened TL is associated with interstitial lung disease (ILD) in individuals with rheumatoid arthritis (RA). This is the largest study to demonstrate and replicate that shortened peripheral blood leukocytes-TL is associated with ILD in patients with RA compared with RA without ILD in a multinational cohort, and short PBL-TL was associated with baseline disease severity in RA-ILD as measured by forced vital capacity percent predicted., Competing Interests: Competing interests: TJD reports grant funding and other support from Bristol Myers Squibb, Genentech, and Bayer and personal fees from Boehringer Ingelheim, unrelated to this study. PA-J reports personal fees from Bristol Myers Squibb, Boehringer Ingelheim, Astra-Zeneca and Medac unrelated to this study. MEW reports grant funding from Amgen, Bristol Myers Squibb, Eli Lilly; personal fees from Bristol Myers Squibb, Sanofi, and Eli Lilly, Abbvie, Arena Pharmaceuticals, CorEvitas, GlaxoSmithKline, Horizon Therapeutics, Pfizer, Scipher Medicine, and Setpoint Medical; and other funding from Scipher Medicine, Can-Fite Biopharma, Inmedix, and VersaPharm, unrelated to this study. NAS reports grant funding from Bristol Myers Squibb, Sanofi, Amgen, Crescendo Bioscience, Eli Lilly, and Mallinckrodt Pharmaceuticals and personal fees from Bristol Myers Squibb, unrelated to this study. RG receives grant support from Canon Medical Systems. HH reports grants from Canon Medical Systems, grants from Konica Minolta Inc, personal fees from Mitsubishi Chemical Co, personal fees from Canon Medical Systems Inc. MN reports grants from AstraZeneca, grants from Daiichi Sankyo, grants from Canon Medical Systems, grants from Merck investigator studies program, personal fees from Daiichi Sankyo, and personal fees from AstraZeneca. PFD has been a clinical investigator for Boehringer Ingelheim, Bristol Myers Squibb, and Genentech and currently works on an Advisory Committee for the FDA. JAS has received research support from Bristol Myers Squibb and performed consultancy for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, and Pfizer unrelated to this work. IOR reports grant funding from Genentech, unrelated to this study. KDD has received investigator-initiated grant funding from Janssen Research and Development and Pfizer, unrelated to this study; in addition, KDD reports serving as consultant for Inova Diagnostics, Inc., Bristol Myers Squibb and Exagen Diagnostics, and he has received free research assays from Inova Diagnostics, Inc., not used for this study; KDD has also received investigator-initiated grant from Janssen and Pfizer that are unrelated to this project. MKD has been the recipient of two investigator-initiated grants from Boehringer Ingelheim and Pfizer, unrelated to this research. PJW reports grants from Genentech, grants and personal fees for advisory board work from Boehringer Ingelheim and Sanofi, personal fees for advisory board work from Blade Pharmaceuticals, grants and personal fees for lectures from Pliant, outside the submitted work. JSL reports grants and other support from the NIH, Galapagos, Boehringer Ingelheim, United Therapeutics, Eleven P15, Bonac, Avalyn and the Pulmonary Fibrosis Foundation, outside the submitted work. PD reports grant funding and other support from Boehringer Ingelheim, Bristol Myers Squibb and Pfizer and personal fees from Bristol Myers Squibb, Sanofi, Lilly, Abbvie, Pfizer, Medac, Novartis, UCB Pharma and Boehringer Ingelheim, unrelated to this study. BC reports grant funding from Boehringer Ingelheim, Bristol Myers Squibb and Roche and personal fees from Astra Zeneca, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, GSK, Novartis, Rochen and Sanofi, unrelated to this study., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To investigate the prevalence and mortality impact of interstitial lung abnormalities (ILAs) in RA and non-RA comparators., Methods: We analysed associations between ILAs, RA, and mortality in COPDGene, a multicentre prospective cohort study of current and past smokers, excluding known interstitial lung disease (ILD) or bronchiectasis. All participants had research chest high-resolution CT (HRCT) reviewed by a sequential reading method to classify ILA as present, indeterminate or absent. RA cases were identified by self-report RA and DMARD use; non-RA comparators had neither an RA diagnosis nor used DMARDs. We examined the association and mortality risk of RA and ILA using multivariable logistic regression and Cox regression., Results: We identified 83 RA cases and 8725 non-RA comparators with HRCT performed for research purposes. ILA prevalence was 16.9% in RA cases and 5.0% in non-RA comparators. After adjusting for potential confounders, including genetics, current/past smoking and other lifestyle factors, ILAs were more common among those with RA compared with non-RA [odds ratio 4.76 (95% CI 2.54, 8.92)]. RA with ILAs or indeterminate for ILAs was associated with higher all-cause mortality compared with non-RA without ILAs [hazard ratio (HR) 3.16 (95% CI 2.11, 4.74)] and RA cases without ILA [HR 3.02 (95% CI 1.36, 6.75)]., Conclusions: In this cohort of smokers, RA was associated with ILAs and this persisted after adjustment for current/past smoking and genetic/lifestyle risk factors. RA with ILAs in smokers had a 3-fold increased all-cause mortality, emphasizing the importance of further screening and treatment strategies for preclinical ILD in RA., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Interstitial lung disease due to rheumatoid arthritis (RA-ILD) affects a substantial minority of patients with RA, inducing life-altering symptoms, impairing quality of life (QOL) and forcing patients to confront the potential for shortened survival. Dyspnoea is the predominant respiratory symptom of RA-ILD and a strong driver of QOL impairment in patients with it. The D12 is a 12-item questionnaire that assesses the physical and affective components of dyspnoea. It was one of a battery of patient-reported outcomes used in the double-blind, placebo-controlled TRAIL 1 trial of pirfenidone for RA-ILD. There is little information on the reliability, validity or responsiveness of the D12 in RA-ILD., Methods: In accordance with COSMIN (COnsensus-based Standards for the selection of health Measurement INstruments) methodology, we conducted analyses on data from the TRAIL 1 trial to assess the measurement properties of the D12., Results: Internal consistency (α=0.95, 0.95, 0.95, 0.95 and 0.96 at baseline, 13, 26, 39 and 52 weeks) and test-retest reliability 0.85 (0.71 to 0.92) exceeded acceptability criteria. Well over the 75% benchmark of hypotheses (43/46=93%) around D12 measurement properties were confirmed. Known-groups validity was supported by significant differences between subgroups of patients with differing levels of dyspnoea (eg, St. George's Respiratory Questionnaire (SGRQ) Activity score ≥50 vs <50, 9.36 (1.27) points, p<0.0001, with a large effect size=1.7) and physiological impairment at baseline. Longitudinal validity was supported by significant associations between D12 and anchor scores over time (eg, at 52 weeks, correlation between D12 change and SGRQ Activity change was 0.54, p<0.0001; between D12 change and Routine Assessment of Patient Index Data (RAPID) Functioning Component was 0.41, p<0.0001). A battery of analyses confirmed the responsiveness of D12 scores for capturing change in dyspnoea over time. We estimated the minimal within-patient change threshold for worsening as 3 points., Conclusions: D12 scores possess acceptable measurement properties in RA-ILD, such that it can be used with confidence in this population to assess dyspnoea severity defined by its physical and affective components. As validation is an ongoing process, and never accomplished in a single study, additional research on the psychometric properties of the D12 in RA-ILD is encouraged., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To establish a framework by which experts define disease subsets in systemic sclerosis associated interstitial lung disease (SSc-ILD)., Methods: A conceptual framework for subclinical, clinical and progressive ILD was provided to 83 experts, asking them to use the framework and classify actual SSc-ILD patients. Each patient profile was designed to be classified by at least four experts in terms of severity and risk of progression at baseline; progression was based on 1-year follow-up data. A consensus was reached if ≥75% of experts agreed. Experts provided information on which items were important in determining classification., Results: Forty-four experts (53%) completed the survey. Consensus was achieved on the dimensions of severity (75%, 60 of 80 profiles), risk of progression (71%, 57 of 80 profiles) and progressive ILD (60%, 24 of 40 profiles). For profiles achieving consensus, most were classified as clinical ILD (92%), low risk (54%) and stable (71%). Severity and disease progression overlapped in terms of framework items that were most influential in classifying patients (forced vital capacity, extent of lung involvement on high resolution chest CT [HRCT]); risk of progression was influenced primarily by disease duration., Conclusions: Using our proposed conceptual framework, international experts were able to achieve a consensus on classifying SSc-ILD patients along the dimensions of disease severity, risk of progression and progression over time. Experts rely on similar items when classifying disease severity and progression: a combination of spirometry and gas exchange and quantitative HRCT., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Competing Interests: ERV is supported by the National Heart, Lung, and Blood Institute (grant number K23 HL150237) and reports consulting and speaking fees from Boehringer Ingelheim; and institutional support received for performing studies on systemic sclerosis for Kadmon, Forbius, Boehringer Ingelheim, Horizon, and Prometheus; all outside the submitted work. JAS is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant numbers R01 AR077607, P30 AR070253, and P30 AR072577), the Rheumatology Research Foundation, the R Bruce and Joan M Mickey Research Scholar Fund, and the Llura Gund Award for Rheumatoid Arthritis Research and Care; has received research support from Bristol Myers Squibb; and performed consultancy for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, and Pfizer; all outside the submitted work. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard University, its affiliated academic health care centres, or the National Institutes of Health. A-MH-V reports consulting fees from ARXX, Boehringer Ingelheim, Genentech, Janssen, Medscape, Roche, and Bayer; speaking fees from ARXX, Boehringer Ingelheim, Janssen, Lilly, Medscape, Merch Sharp & Dohme, and Roche; grants from Boehringer Ingelheim and Jannsen; support for attending meetings or travel from Boehringer Ingelheim and Janssen; and a previous role as Secretary in the European Alliance of Associations for Rheumatology; all outside the submitted work. TJD is supported by the National Heart, Lung, and Blood Institute; reports grant support from Bristol Myers Squibb; consulting fees from Boehringer Ingelheim and LEK consulting; has been part of a clinical trial funded by Genentech; and reports support for attending meetings or travel and payment for lectures for AURA medical. PE reports consulting fees from Bristol Myers Squibb, Boehringer Ingelheim, Galapagos, Eli Lilly, Novartis, and Gilead; payments for lectures from Abbvie, Astra-Zeneca, Bristol Myers Squibb, Boehringer Ingelheim, Galapagos, Gilead, Eli Lilly, Novartis; support for attending meetings or travel from Eli Lilly and Novartis; and participation on a data safety monitoring board or advisory board for AstraZeneca. PD is supported by the Société Française de Rhumatologie; has received research support from Bristol Myers Squibb, Galapagos, Chugai, and Pfizer; has performed consultancy for AbbVie, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, Novartis, Galapagos, and Pfizer; and reports participation on a data safety and monitoring board for Bristol Myer Squibb and Boehringer Ingelheim; all outside of the submitted work. The content is solely the responsibility of the authors and does not necessarily represent the official views of Paris cité University, its affiliated academic health care centres, or the Assistance Publique des Hôpitaux de Paris. PE and PD contributed equally to this manuscript.

Background: To identify fine specificity anti-citrullinated protein antibodies (ACPA) associated with incident rheumatoid arthritis-associated interstitial lung disease (RA-ILD)., Methods: This nested case-control study within the Brigham RA Sequential Study matched incident RA-ILD cases to RA-noILD controls on time of blood collection, age, sex, RA duration, and rheumatoid factor status. A multiplex assay measured ACPA and anti-native protein antibodies from stored serum prior to RA-ILD onset. Logistic regression models calculated odds ratios (OR) with 95% confidence intervals (CI) for RA-ILD, adjusting for prospectively-collected covariates. We estimated optimism-corrected area under the curves (AUC) using internal validation. Model coefficients generated a risk score for RA-ILD., Findings: We analyzed 84 incident RA-ILD cases (mean age 67 years, 77% female, 90% White) and 233 RA-noILD controls (mean age 66 years, 80% female, 94% White). We identified six fine specificity antibodies that were associated with RA-ILD. The antibody isotypes and targeted proteins were: IgA2 to citrullinated histone 4 (OR 0.08 per log-transformed unit, 95% CI 0.03-0.22), IgA2 to citrullinated histone 2A (OR 4.03, 95% CI 2.03-8.00), IgG to cyclic citrullinated filaggrin (OR 3.47, 95% CI 1.71-7.01), IgA2 to native cyclic histone 2A (OR 5.52, 95% CI 2.38-12.78), IgA2 to native histone 2A (OR 4.60, 95% CI 2.18-9.74), and IgG to native cyclic filaggrin (OR 2.53, 95% CI 1.47-4.34). These six antibodies predicted RA-ILD risk better than all clinical factors combined (optimism-corrected AUC=0·84 versus 0·73). We developed a risk score for RA-ILD combining these antibodies with the clinical factors (smoking, disease activity, glucocorticoid use, obesity). At 50% predicted RA-ILD probability, the risk scores both without (score=2·6) and with (score=5·9) biomarkers achieved specificity ≥93% for RA-ILD., Interpretation: Specific ACPA and anti-native protein antibodies improve RA-ILD prediction. These findings implicate synovial protein antibodies in the pathogenesis of RA-ILD and suggest clinical utility in predicting RA-ILD once validated in external studies., Funding: National Institutes of Health., Competing Interests: Declaration of interests: Dr. Yoshida has received consulting fees from OM1 unrelated to this work. Dr. Davis has received research support from Pfizer, has a patent pending for assessing and treating arthritis and serve on a data safety monitoring board for a rheumatoid arthritis clinical trial sponsored by the National Institutes of Health, all unrelated to this work. Dr. Dellaripa has received consulting fees from Boehringer Ingelheim, Bristol Myers Squibb, and Genentech and receives royalties from UpToDate unrelated to this work. Dr. Hatabu has received research support from Canon Medical Systems and Konica-Minolta as well as consulting fees from Canon Medical Systems and the Mitsubishi Chemical Company unrelated to this work. Dr. Nishino has received research support from AstraZeneca, Canon Medical Systems, and Daiichi Sankyo, and consulting fees from AstraZeneca, Daiichi Sankyo unrelated to this work. Dr. Sokolove is currently an employee at GlaxoSmithKline and owns shares in GlaxoSmithKline, and his work on this project preceded this employment. Dr. Weinblatt has received research support from Amgen, Bristol Myers Squibb, Eli Lilly, Aqtual, and Janssen; consultancy fees from AbbVie, Aclaris, Amgen, Aqtual, Bayer, Bristol Myers Squibb, CorEvitas, EqRX, Genosco, GlaxoSmithKline, Gilead, Johnson & Johnson, Kyvrena, Eli Lilly, Pfizer, Rani, Revolo, Sanofi, Scipher, SciRom, SetPoint, and Tremeau; stock options from Canfite, Inmedex, and Scipher, all unrelated to this work. Dr. Shadick has received research grants from AbbVie, Amgen, Aqtual, Bristol Myers Squibb, Eli Lilly, and Mallinckrodt unrelated to this work. Dr. Doyle has received research support from Bristol Myers Squibb; consulting fees from Boehringer Ingelheim and L.E.K. consulting; speaking fees and travel support from Aura; and has been part of a clinical trial funded by Genentech, unrelated to this work. Dr. Sparks has received research support from Bristol Myers Squibb and performed consultancy for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, and Pfizer unrelated to this work.

Background: The risk factors and clinical outcomes of quantitative interstitial abnormality progression over time have not been characterized., Research Questions: What are the associations of quantitative interstitial abnormality progression with lung function, exercise capacity, and mortality? What are the demographic and genetic risk factors for quantitative interstitial abnormality progression?, Study Design and Methods: Quantitative interstitial abnormality progression between visits 1 and 2 was assessed from 4,635 participants in the Genetic Epidemiology of COPD (COPDGene) cohort and 1,307 participants in the Pittsburgh Lung Screening Study (PLuSS) cohort. We used multivariable linear regression to determine the risk factors for progression and the longitudinal associations between progression and FVC and 6-min walk distance, and Cox regression models for the association with mortality., Results: Age at enrollment, female sex, current smoking status, and the MUC5B minor allele were associated with quantitative interstitial abnormality progression. Each percent annual increase in quantitative interstitial abnormalities was associated with annual declines in FVC (COPDGene: 8.5 mL/y; 95% CI, 4.7-12.4 mL/y; P < .001; PLuSS: 9.5 mL/y; 95% CI, 3.7-15.4 mL/y; P = .001) and 6-min walk distance, and increased mortality (COPDGene: hazard ratio, 1.69; 95% CI, 1.34-2.12; P < .001; PLuSS: hazard ratio, 1.28; 95% CI, 1.10-1.49; P = .001)., Interpretation: The objective, longitudinal measurement of quantitative interstitial abnormalities may help identify people at greatest risk for adverse events and most likely to benefit from early intervention., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Rapid identification of potentially life-threatening blood stream infections (BSI) improves clinical outcomes, yet conventional blood culture (BC) identification methods require ~24-72 hours of liquid culture, plus 24-48 hours to generate single colonies on solid media suitable for identification by mass spectrometry (MS). Newer rapid centrifugation techniques, such as the Bruker MBT-Sepsityper® IVD, replace culturing on solid media and expedite the diagnosis of BCs but frequently demonstrate reduced sensitivity for identifying clinically significant Gram-positive bacterial or fungal infections. This study introduces a protocol that utilises the broad-range binding properties of an engineered version of mannose-binding lectin linked to the Fc portion of immunoglobulin (FcMBL) to capture and enrich pathogens combined with matrix-assisted laser desorption-ionisation time-of-flight (MALDI-TOF) MS for enhanced infection identification in BCs. The FcMBL method identified 94.1% (64 of 68) of clinical BCs processed, with a high sensitivity for both Gram-negative and Gram-positive bacteria (94.7 and 93.2%, respectively). The FcMBL method identified more patient positive BCs than the Sepsityper® (25 of 25 vs 17 of 25), notably with 100% (3/3) sensitivity for clinical candidemia, compared to only 33% (1/3) for the Sepsityper®. Additionally, during inoculation experiments, the FcMBL method demonstrated a greater sensitivity, identifying 100% (24/24) of candida to genus level and 9/24 (37.5%) top species level compared to 70.8% (17/24) to genus and 6/24 to species (25%) using the Sepsityper®. This study demonstrates that capture and enrichment of samples using magnetic FcMBL-conjugated beads is superior to rapid centrifugation methods for identification of BCs by MALDI-TOF MS. Deploying the FcMBL method therefore offers potential clinical benefits in sensitivity and reduced turnaround times for BC diagnosis compared to the standard Sepsityper® kit, especially for fungal diagnosis., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: D.E.I. has equity in BOA Biomedical, consults and leads their SAB. M.S. has equity & consults for BOA Biomedical. J.A.H. & S.L.L. consult for BOA Biomedical. M.T.M. and G.A.D. are employees of BOA Biomedical. All other authors declare that they have not competing financial interests., (Copyright: © 2022 Kite et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: Patients at high risk of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) would benefit from being identified before the onset of respiratory symptoms; this can be done by screening patients with the use of chest high-resolution computed tomography (HRCT). Our objective was to develop and validate a risk score for patients who have subclinical RA-ILD., Methods: Our study included a discovery population and a replication population from 2 prospective RA cohorts (ESPOIR and TRANSLATE2, respectively) without pulmonary symptoms who had received chest HRCT scans. All patients were genotyped for MUC5B rs35705950. After multiple logistic regression, a risk score based on independent risk factors for subclinical RA-ILD was developed in the discovery population and tested for validation in the replication population., Results: The discovery population included 163 patients with RA, and the replication population included 89 patients with RA. The prevalence of subclinical RA-ILD was 19.0% and 16.9%, respectively. In the discovery population, independent risk factors for subclinical RA-ILD were presence of the MUC5B rs35705950 T allele (odds ratio [OR] 3.74 [95% confidence interval (95% CI) 1.37, 10.39]), male sex (OR 3.93 [95% CI 1.40, 11.39]), older age at RA onset (for each year, OR 1.10 [95% CI 1.04, 1.16]), and increased mean Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (for each unit, OR 2.03 [95% CI 1.24, 3.42]). We developed and validated a derived risk score with receiver operating characteristic areas under the curve of 0.82 (95% CI 0.70-0.94) for the discovery population and 0.78 (95% CI 0.65-0.92) for the replication population. Excluding MUC5B rs35705950 from the model provided a lower goodness of fit (likelihood ratio test, P = 0.01)., Conclusion: We developed and validated a risk score that could help identify patients at high risk of subclinical RA-ILD. Our findings support an important contribution of MUC5B rs35705950 to subclinical RA-ILD risk., (© 2022 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Background: The objective was to estimate risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in pregnancy and assess adverse maternal and perinatal outcomes., Methods: We used a population-based, retrospective cohort of all pregnancies with a live birth or fetal death in Florida from 1 March 2020 to 30 April 2021. Coronavirus disease 2019 (COVID-19) case reports were matched to vital registries. Outcomes assessed were risk of infection in pregnancy, preterm birth, maternal or neonatal admission to an intensive care unit (ICU), perinatal or fetal death, and maternal death. Modified Poisson and multinomial logistic regression models were used to derive relative risk estimates., Results: Of 234 492 women with a live birth or fetal death during the study period, 12 976 (5.5%) were identified with COVID-19 during pregnancy. Risk factors for COVID-19 in pregnancy included Hispanic ethnicity (relative risk [RR] = 1.89), Black race (RR = 1.34), being unmarried (RR = 1.04), and being overweight or obese pre-pregnancy (RR = 1.08-1.32). COVID-19 during pregnancy was associated with preterm birth (RR = 1.31), Cesarean delivery (RR = 1.04), and neonatal (RR = 1.17) and maternal (RR = 3.10) ICU admission; no association was found with increased risk of perinatal (RR = 0.72) or fetal death (RR = 0.86). Women infected during any trimester showed increased risk of preterm birth. Fourteen maternal deaths were identified among COVID-19 cases; of those who died, 12 were obese. The death rate per 10 000 was 22.09 among obese and 1.22 among non-obese gravida with COVID-19 during pregnancy (RR = 18.99, P = .001)., Conclusions: Obesity is a risk factor for SARS-CoV-2 infection in pregnancy and for more severe COVID-19 illness among pregnant women. SARS-CoV-2 infection is associated with preterm birth., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2022.)

Although interstitial lung disease (ILD) causes significant morbidity and mortality in rheumatoid arthritis (RA), it is difficult to predict the development or progression of ILD, emphasising the need for improved discovery through minimally invasive diagnostic tests. Aptamer-based proteomic profiling was used to assess 1321 proteins from 159 patients with rheumatoid arthritis with interstitial lung disease (RA-ILD), RA without ILD, idiopathic pulmonary fibrosis and healthy controls. Differential expression and gene set enrichment analyses revealed molecular signatures that are strongly associated with the presence and severity of RA-ILD and provided insight into unexplored pathways of disease. These warrant further study as non-invasive diagnostic tools and future therapeutic targets., Competing Interests: Competing interests: The authors have reported the following conflicts of interest, all outside the submitted work: ST reports medical advisory group membership of Novo Nordisk and board membership at Droobi Health, Qatar. RG receives grant support from Canon Medical Systems. HH reports grants from Canon Medical Systems and Konica Minolta, and personal fees from Mitsubishi Chemical Co and Canon Medical Systems Inc. MN reports grants from AstraZeneca, Daiichi Sankyo, Canon Medical Systems, Merck investigator studies program; personal fees from Daiichi Sankyo and AstraZeneca. MEW receives research support from Amgen, Bristol Myers Squibb and Eli Lilly and consultation fees from AbbVie, Aclaris, Amgen, Arena, Bayer, Bristol Myers Squibb, Corvitas, Eqrx, Genosco, GSK, Gilead, Horizon, Johnson & Johnson, Kiniksa, Lilly, Novartis, Pfizer, Rami Therapeutics, R Pharma, Roche, Sanofi, Scipher, Sci Rhom, Set Point and Tremeau. He holds stock/stock options of CanFite, Inmedix, Vorso and Scipher. NAS reports grants and other support from Bristol-Myers Squibb, grants from Mallinckrodt, Sanofi, Crescendo Biosciences, Lilly and Amgen. PFD reports grants from Bristol-Myers Squibb and Genentech, and other support from Boehringer Ingelheim. AMKC is a cofounder and equity stock holder for Proterris, which develops therapeutic uses for carbon monoxide, and also has a use patent on CO and a patent in chronic obstructive pulmonary disease. EYK is a member of the steering committees for and receives no financial remuneration from NCT04409834 (Prevention of arteriovenous thrombotic events in critically ill COVID-19 patients, TIMI group) and REMAP-CAP ACE2 renin–angiotensin system modulation domain, and receives unrelated research funding from Bayer AG, Roche Pharma Research and Early Development, Windtree Therapeutics, the US National Institutes of Health, the US Agency for International Development, the American Heart Association, American Lung Association and the Bell Family Fund. IOR reports grants from Genentech. FJM reports personal fees, non-financial support and other support from AstraZeneca, other support from Afferent/Merck, personal fees, non-financial support and other support from Boehringer Ingelheim, other support from Bristol Myers Squibb, other support from Chiesi, personal fees and non-financial support from the Canadian Respiratory Society, personal fees and non-financial support from CME Outfitters, personal fees and non-financial support from CSL Behring, personal fees from Dartmouth University, personal fees from France Foundation, personal fees from Gala, personal fees and non-financial support from Genentech, grants, personal fees, non-financial support and other support from GlaxoSmithKline, personal fees and non-financial support from Inova Fairfax, personal fees and non-financial support from MD Magazine, personal fees and non-financial support from NYP Methodist Hospital Brooklyn, personal fees and non-financial support from Miller Communications, personal fees and non-financial support from National Association for Continuing Education/Integritas, other support from Nitto, personal fees and non-financial support from Novartis, personal fees from New York University, personal fees and non-financial support from Patara/Respivant, personal fees from Pearl, personal fees and non-financial support from Peer View, personal fees from Physicians Education Resource, personal fees from ProMedior, personal fees and non-financial support from Rare Diseases Healthcare Communications, personal fees from Rockpointe Communications, personal fees and non-financial support from Sanofi/Regeneron, other support from Biogen, personal fees and non-financial support from Sunovion, personal fees and non-financial support from Teva, other support from two XAR, personal fees from University of Birmingham Alabama, personal fees from UpToDate, non-financial support from Veracyte, personal fees from Vindico, personal fees and non-financial support from WebMD/MedScape, non-financial support and other support from Zambon, non-financial support from ProTerrix Bio, and personal fees from IQVIA, Raziel, Abvie and Verona. TJD has received grant support from Bristol Myers Squibb, consulting fees from Boehringer Ingelheim and L.E.K. consulting, and has been part of a clinical trial funded by Genentech. The remaining authors have reported no conflicts of interest., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Pulmonary disease is a common extraarticular manifestation of RA associated with increased morbidity and mortality. No current strategies exist for screening this at-risk population for parenchymal lung disease, including emphysema and interstitial lung disease (ILD)., Methods: RA patients without a diagnosis of ILD or chronic obstructive pulmonary disease underwent prospective and comprehensive clinical, laboratory, functional and radiological evaluations. High resolution CT (HRCT) scans were scored for preclinical emphysema and preclinical ILD and evaluated for other abnormalities., Results: Pulmonary imaging and/or functional abnormalities were identified in 78 (74%) of 106 subjects; 45% had preclinical parenchymal lung disease. These individuals were older with lower diffusion capacity but had similar smoking histories compared with no disease. Preclinical emphysema (36%), the most commonly detected abnormality, was associated with older age, higher anti-cyclic citrullinated peptide antibody titres and diffusion abnormalities. A significant proportion of preclinical emphysema occurred among never smokers (47%) with a predominantly panlobular pattern. Preclinical ILD (15%) was not associated with clinical, laboratory or functional measures., Conclusion: We identified a high prevalence of undiagnosed preclinical parenchymal lung disease in RA driven primarily by isolated emphysema, suggesting that it may be a prevalent and previously unrecognized pulmonary manifestation of RA, even among never smokers. As clinical, laboratory and functional evaluations did not adequately identify preclinical parenchymal abnormalities, HRCT may be the most effective screening modality currently available for patients with RA., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To investigate demographic, lifestyle, and serologic risk factors for isolated rheumatoid arthritis (RA)-associated bronchiectasis (RA-BR) that is not a result of interstitial lung disease (ILD)., Methods: We performed a case-control study using patients with RA from the Mass General Brigham Biobank. We reviewed the records of all patients with RA meeting the 2010 American College of Rheumatology/European Alliance of Associations for Rheumatology criteria with computed tomography (CT) chest imaging to identify RA-BR cases and controls with RA and RA-related lung disease. For each patient, the CT chest imaging that was performed closest to enrollment was independently reviewed by 2 radiologists for the presence of RA-related lung diseases. Cases had clinical and radiologic evidence of RA-BR without interstitial lung abnormalities on imaging. Controls had RA and no evidence of bronchiectasis or ILD. We examined the associations between demographic, lifestyle, and serologic factors with RA-BR using multivariable logistic regression., Results: We identified 57 cases of isolated RA-BR and 360 RA controls without RA-related lung disease. In multivariable models, RA-BR was associated with older age at RA onset (OR 1.37 per 10 years, 95% CI 1.02-1.82), lower BMI at RA diagnosis (OR 0.94 per kg/m 2 , 95% CI 0.89-0.99), seropositive RA (OR 3.96, 95% CI 1.84-8.53), positive rheumatoid factor (OR 4.40, 95% CI 2.14-9.07), and positive anticyclic citrullinated peptide (OR 3.47, 95% CI 1.65-7.31). Higher titers of RA-related autoantibodies were associated with higher odds of RA-BR., Conclusion: Seropositivity, older age at RA diagnosis, and lower BMI at RA onset were associated with isolated bronchiectasis in RA that was not a result of ILD. These findings expand the list of potential risk factors for RA-BR and suggest a pathogenic link between airway inflammation and RA-related autoantibodies., (Copyright © 2022 by the Journal of Rheumatology.)

Objective: We aimed to determine whether specific respiratory tract diseases are associated with increased rheumatoid arthritis (RA) risk., Methods: This case-control study within the Mass General Brigham Biobank matched newly diagnosed RA cases to 3 controls on age, sex, and electronic health record history. We identified RA using a validated algorithm and confirmed by medical record review. Respiratory tract disease exposure required 1 inpatient or 2 outpatient codes at least 2 years before the index date of RA clinical diagnosis or matched date. Logistic regression models calculated ORs for RA with 95% CIs, adjusting for confounders. We then stratified by serostatus ("seropositive" was positive rheumatoid factor and/or anticitrullinated protein antibodies) and smoking., Results: We identified 741 RA cases and 2223 controls (both median age 55, 76% female). Acute sinusitis (OR 1.61, 95% CI 1.05-2.45), chronic sinusitis (OR 2.16, 95% CI 1.39-3.35), and asthma (OR 1.39, 95% CI 1.03-1.87) were associated with increased risk of RA. Acute respiratory tract disease burden during the preindex exposure period was also associated with increased RA risk (OR 1.30 per 10 codes, 95% CI 1.08-1.55). Acute pharyngitis was associated with seronegative (OR 1.68, 95% CI 1.02-2.74) but not seropositive RA; chronic rhinitis/pharyngitis was associated with seropositive (OR 2.46, 95% CI 1.01-5.99) but not seronegative RA. Respiratory tract diseases tended towards higher associations in smokers, especially > 10 pack-years (OR 1.52, 95% CI 1.02-2.27, P = 0.10 for interaction)., Conclusion: Acute and chronic sinusitis, pharyngitis, and acute respiratory burden increased RA risk. The mucosal paradigm of RA pathogenesis may involve the upper respiratory tract., (Copyright © 2022 by the Journal of Rheumatology.)

Rheumatoid arthritis (RA)-associated interstitial lung disease (RA-ILD) is the most common pulmonary complication of RA, increasing morbidity and mortality. Anti-citrullinated protein antibodies have been associated with the development and progression of both RA and fibrotic lung disease; however, the role of protein citrullination in RA-ILD remains unclear. Here, we demonstrate that the expression of peptidylarginine deiminase 2 (PAD2), an enzyme that catalyzes protein citrullination, is increased in lung homogenates from subjects with RA-ILD and their lung fibroblasts. Chemical inhibition or genetic knockdown of PAD2 in RA-ILD fibroblasts attenuated their activation, marked by decreased myofibroblast differentiation, gel contraction, and extracellular matrix gene expression. Treatment of RA-ILD fibroblasts with the proteoglycan syndecan-2 (SDC2) yielded similar antifibrotic effects through regulation of PAD2 expression, phosphoinositide 3-kinase/Akt signaling, and Sp1 activation in a CD148-dependent manner. Furthermore, SDC2-transgenic mice exposed to bleomycin-induced lung injury in an inflammatory arthritis model expressed lower levels of PAD2 and were protected from the development of pulmonary fibrosis. Together, our results support a SDC2-sensitive profibrotic role for PAD2 in RA-ILD fibroblasts and identify PAD2 as a promising therapeutic target of RA-ILD., (© 2022. The Author(s).)

Objective: To investigate the association between timing of respiratory tract diseases and risk of rheumatoid arthritis (RA)., Methods: This case-control study using the Mass General Brigham Biobank matched incident RA cases, confirmed by ACR/EULAR criteria, with at least seven years preceding electronic health record (EHR) data to three controls on age, sex, and EHR history from RA diagnosis (index date). We ascertained timing (>0-5 years/>5-10 years/>10 years) of the first documented respiratory tract disease prior to index date using diagnosis codes. We estimated odds ratios (OR) with 95% confidence intervals (CI) for RA for each respiratory exposure using logistic regression models, adjusting for potential confounders. We also conducted a stratified analysis by serostatus and smoking., Results: We identified 625 incident RA cases (median 56 years, 75% female, 57% seropositive) and 1,875 controls. Acute sinusitis was associated with RA only in the >5 to 10 years before RA (OR 3.90, 95% CI:1.90,8.01). In contrast, pneumonia was associated with RA only in the >0 to 5 years before RA (OR 1.73, 95% CI:1.00,3.00), and chronic respiratory tract diseases only >10 years before RA (OR 1.43, 95% CI:1.00,2.05). All respiratory tract diseases tended to show a stronger association with seronegative RA than seropositive RA, although the interaction was statistically significant only for chronic sinusitis (p=0.04). Respiratory diseases showed a nonsignificantly stronger association among smokers than nonsmokers., Conclusion: Sinusitis and other respiratory diseases are associated with increased risk of RA, especially 5 years before RA onset. RA may begin many years before clinical onset., Competing Interests: Declaration of Competing Interest None related to this work., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: Anti-synthetase syndrome (ASSD) is a heterogeneous autoimmune disease characterised by multi-system involvement with a wide variety of manifestations. Validated classification criteria are necessary to improve recognition and prevent misclassification, especially given the lack of reliable and standardised autoantibody testing. We systematically reviewed the literature to analyse proposed ASSD criteria, characteristics, and diagnostic performance., Methods: We searched PubMed and Embase databases (01/01/1984 to 06/11/2018) and the ACR and EULAR meeting abstracts (2017-2018). Sensitivities, specificities, positive, negative likelihood ratios and risk of bias were calculated for ASSD criteria and key variables reported in the literature. We performed meta-analysis when appropriate., Results: We retrieved 4,358 studies. We found 85 proposed ASSD criteria from a total of 82 studies. All but one study included anti-synthetase autoantibody (ARS) positivity in the ASSD criteria. Most studies required only one ASSD feature plus anti-ARS to define ASSD (n=64, 78%), whereas 16 studies required more than one ASSD variable plus anti-ARS. The only criteria not including anti-ARS positivity required 5 ASSD clinical features. We found limited data and wide variability in the diagnostic performance of each variable and definition proposed in the literature. Given these limitations we only meta-analysed the performance of individual muscle biopsy and clinical variables in diagnosing ASSD, which performed poorly., Conclusions: The current ASSD criteria include a variety of serological, clinical, and histological features with wide variability amongst proposed definitions and the performance of these definitions has not been tested. This systematic literature review suggests the need for additional data and consensus-driven classification criteria for ASSD.

Objective: To investigate the independent relationship of rheumatoid arthritis (RA) to the type and severity of pulmonary patterns on spirometry compared to the pulmonary patterns in general population controls., Methods: In this cross-sectional study, we investigated the association of RA with pulmonary function measures on spirometry among subjects in the UK Biobank who underwent spirometry for research purposes. RA cases were identified based on self-report and current disease-modifying antirheumatic drug/glucocorticoid use. Controls were subjects without RA from the general population. Outcome measures included continuous forced expiratory volume in 1 second percent predicted (FEV 1 %) and forced vital capacity percent predicted (FVC%), type of spirometric pattern (restrictive or obstructive), and severity of the restrictive or obstructive pattern. We used multivariable regression to estimate the effects in RA cases compared to the effects in controls, adjusting for age, sex, body mass index, and smoking status/pack-years., Results: Among 350,776 analyzed subjects who underwent spirometry (mean age 56.3 years; 55.8% female; 45.5% ever smokers), we identified 2,008 cases of treated RA. In multivariable analyses, RA was associated with lower FEV 1 % (β = -2.93 [95% confidence interval (95% CI) -3.63, -2.24]), FVC% (β = -2.08 [95% CI -2.72, -1.45]), and FEV 1 /FVC (β = -0.008 [95% CI -0.010, -0.005]) compared to controls. RA was additionally associated with restrictive patterns (odds ratio [OR] 1.36 [95% CI 1.21, 1.52]) and obstructive patterns (OR 1.21 [95% CI 1.07, 1.37]) independent of confounders, and was most strongly associated with severe restrictive and obstructive patterns., Conclusion: RA is associated with increased odds of restrictive and obstructive patterns, and this relationship is not explained by confounders, including smoking status. In addition to restrictive lung disease, clinicians should also be aware that airway obstruction may be a pulmonary manifestation of RA., (© 2021, American College of Rheumatology.)

Objectives: We performed a systematic review and meta-analysis for the prevalence and risk factors of rheumatoid arthritis-related bronchiectasis (RA-BR)., Methods: We queried PubMed and EMBASE databases to identify published literature related to prevalence and risk factors for RA-BR among patients with RA. Data extraction included study design, country, year, method of RA-BR detection, RA characteristics, numerator of RA-BR cases and denominator of patients with RA, and associations with RA-BR presence. We performed a meta-analysis using random or fixed effects models to estimate the prevalence of RA-BR among RA., Results: Out of a total of 253 studies, we identified 41 total studies that reported on prevalence (n = 34), risk factors (n = 5), or both (n = 2). The included studies had heterogeneous methods to identify RA-BR. Among the 36 studies reporting prevalence, 608 RA-BR cases were identified from a total of 8569 patients with RA. In the meta-analysis, the pooled overall prevalence of RA-BR among RA was 18.7% (95%CI 13.7-24.3%) using random effects and 3.8% (95%CI 3.3-4.2%) using fixed effects. Among studies that used high-resolution chest computed tomography (HRCT) imaging, the prevalence of RA-BR was 22.6% (95%CI 16.8-29.0%) using random effects. When only considering retrospective studies (n = 12), the pooled prevalence of RA-BR among RA was 15.5% (95%CI 7.5-25.5%); among prospective studies (n = 24), the pooled prevalence was 20.7% (95% CI 14.7-27.4%). Risk factors for RA-BR included older age, longer RA duration, genetics (CFTR and HLA), and undetectable circulating mannose binding lectin (MBL) as a biomarker., Conclusion: In this systematic review and meta-analysis, the prevalence of RA-BR was nearly 20% among studies with HRCT imaging, suggesting that bronchiectasis may be a common extra-articular feature of RA. Relatively few factors have been associated with RA-BR. Future studies should standardize methods to identify RA-BR cases and investigate the natural history and clinical course given the relatively high prevalence among RA., Competing Interests: Declaration of Competing Interest Dr. Sparks reports research support from Amgen and Bristol-Myers Squibb and consultancy fees from Bristol-Myers Squibb, Gilead, Inova, Janssen, Optum, and Pfizer. Dr. Doyle reports research support from Bristol Myers Squibb, consulting fees from Boehringer Ingelheim, and has been involved in clinical trials funded by Bristol Myers Squibb and Genentech. Dr. Shadick reports research support from Bristol-Myers Squibb, Amgen, Eli Lilly, Mallinckrodt, and Sanofi and consulting fees from Bristol-Myers Squibb. All other authors report no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: This study sought to determine the prognostic significance of the WHO-defined glioma molecular subgroups along with additional alterations, including MGMT promoter methylation and mutations in ATRX , CIC , FUBP1 , TERT , and TP53 , in NRG/RTOG 0424 using long-term follow-up data., Methods: Mutations were determined using an Ion Torrent sequencing panel. 1p/19q co-deletion and MGMT promoter methylation were determined by Affymetrix OncoScan and Illumina 450K arrays. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and tested using the log-rank test. Hazard ratios were calculated using the Cox proportional hazard model. Multivariable analyses (MVAs) included patient pretreatment characteristics., Results: We obtained complete molecular data to categorize 80/129 eligible patients within the WHO subgroups. Of these, 26 (32.5%) were IDH mutant/co-deleted, 28 (35%) were IDH mutant/non-co-deleted, and 26 (32.5%) were IDH wild-type. Upon single-marker MVA, both IDH mutant subgroups were associated with significantly better OS and PFS ( P values < .001), compared with the IDH wild-type subgroup. MGMT promoter methylation was obtained on 76 patients, where 58 (76%) were methylated and 18 (24%) were unmethylated. Single-marker MVAs demonstrated that MGMT promoter methylation was statistically significant for OS ( P value < .001) and PFS ( P value = .003). In a multimarker MVA, one WHO subgroup comparison ( IDH mutant/co-deleted v IDH wild-type) was significant for OS ( P value = .045), whereas MGMT methylation did not retain significance., Conclusion: This study reports the long-term prognostic effect of the WHO molecular subgroups, MGMT promoter methylation, and other mutations in NRG/RTOG 0424. These results demonstrate that the WHO molecular classification and MGMT both serve as strong prognostic indicators, but that MGMT does not appear to add statistically significant prognostic value to the WHO subgrouping, above and beyond IDH and 1p/19q status., Competing Interests: Stephanie L. Pugh Research Funding: Pfizer, Millennium Glenn J. Lesser Honoraria: SDP Oncology Consulting or Advisory Role: Cancer Expert Now, Agios, Incysus Research Funding: Novocure, Oblato, Denovo Biopharma, Global Coalition for Adaptive Research Other Relationship: NCI, ASCO David R. Macdonald Research Funding: Celgene, Servier Erica H. Bell Patents, Royalties, Other Intellectual Property: US20180002762A1 Joseph P. McElroy Employment: Pfizer Cynthia D. Timmers Employment: Incyte Stock and Other Ownership Interests: Array BioPharma, Seattle Genetics, Exact Sciences, Incyte, Arbutus Biopharma, PDS Biotechnology Consulting or Advisory Role: Ventana Medical Systems C. Leland Rogers Employment: Barrow Neurological Institute, GammaWest Cancer Services Stock and Other Ownership Interests: GT Technologies Maria Werner-Wasik Stock and Other Ownership Interests: Illumina Honoraria: AstraZeneca Patents, Royalties, Other Intellectual Property: Signal transduction inhibitor in lymphoma Hsiang-Hsuan Michael Yu Honoraria: UpToDate, Elsevier, Sermo, Guidepoint Global Consulting or Advisory Role: Novocure Speakers' Bureau: BrainLAB Research Funding: Bristol Myers Squibb/Sanofi, Merck Travel, Accommodations, Expenses: BrainLAB David P. D'Souza Consulting or Advisory Role: AbbVie Nadia N. Laack Research Funding: Bristol Myers Squibb Minesh P. Mehta Leadership: Oncoceutics Stock and Other Ownership Interests: Chimerix Consulting or Advisory Role: Tocagen, Karyopharm Therapeutics, Mevion Medical Systems, ZappRx, Sapience Therapeutics Patents, Royalties, Other Intellectual Property: WARF patent 14/934,27, Topical Vasoconstritor Preparations and Methods for Protecting Cells During Cancer Chemotherapy and Radiotherapy Uncompensated Relationships: Xcision Medical Systems, ViewRay Arnab Chakravarti Research Funding: Varian Medical Systems No other potential conflicts of interest were reported. Stephanie L. Pugh Research Funding: Pfizer, Millennium Glenn J. Lesser Honoraria: SDP Oncology Consulting or Advisory Role: Cancer Expert Now, Agios, Incysus Research Funding: Novocure, Oblato, Denovo Biopharma, Global Coalition for Adaptive Research Other Relationship: NCI, ASCO David R. Macdonald Research Funding: Celgene, Servier Erica H. Bell Patents, Royalties, Other Intellectual Property: US20180002762A1 Joseph P. McElroy Employment: Pfizer Cynthia D. Timmers Employment: Incyte Stock and Other Ownership Interests: Array BioPharma, Seattle Genetics, Exact Sciences, Incyte, Arbutus Biopharma, PDS Biotechnology Consulting or Advisory Role: Ventana Medical Systems C. Leland Rogers Employment: Barrow Neurological Institute, GammaWest Cancer Services Stock and Other Ownership Interests: GT Technologies Maria Werner-Wasik Stock and Other Ownership Interests: Illumina Honoraria: AstraZeneca Patents, Royalties, Other Intellectual Property: Signal transduction inhibitor in lymphoma Hsiang-Hsuan Michael Yu Honoraria: UpToDate, Elsevier, Sermo, Guidepoint Global Consulting or Advisory Role: Novocure Speakers' Bureau: BrainLAB Research Funding: Bristol Myers Squibb/Sanofi, Merck Travel, Accommodations, Expenses: BrainLAB David P. D'Souza Consulting or Advisory Role: AbbVie Nadia N. Laack Research Funding: Bristol Myers Squibb Minesh P. Mehta Leadership: Oncoceutics Stock and Other Ownership Interests: Chimerix Consulting or Advisory Role: Tocagen, Karyopharm Therapeutics, Mevion Medical Systems, ZappRx, Sapience Therapeutics Patents, Royalties, Other Intellectual Property: WARF patent 14/934,27, Topical Vasoconstritor Preparations and Methods for Protecting Cells During Cancer Chemotherapy and Radiotherapy Uncompensated Relationships: Xcision Medical Systems, ViewRay Arnab Chakravarti Research Funding: Varian Medical Systems No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

Objective: We aimed to investigate the prevalence, incidence and cause-specific mortality of RA-associated interstitial lung disease (RA-ILD) among older US patients with RA., Methods: We performed a nationwide cohort study using Medicare claims data (parts A, B and D for 2008-2017). RA was identified with a validated algorithm using RA diagnosis codes and DMARD prescription. RA-ILD was identified with a validated algorithm using ILD diagnosis codes by a rheumatologist/pulmonologist. RA-ILD was categorized as prevalent or incident relative to the initial RA observation (baseline/index date). We compared the total mortality of RA-ILD to RA without ILD using multivariable Cox regression, adjusting for baseline covariates. For cause-specific mortality, Fine and Gray subdistribution hazard ratios (sdHRs) were estimated to handle competing risks of alternative mortality causes., Results: Among 509 787 RA patients (mean age 72.6 years, 76.2% female), 10 306 (2.0%) had prevalent RA-ILD at baseline. After baseline, 13 372 (2.6%) developed RA-ILD during 1 873 127 person-years of follow-up (median 3.0 years/person). During follow-up, 38.7% of RA-ILD patients died compared with 20.7% of RA patients without ILD. After multivariable adjustment, RA-ILD had an HR of 1.66 (95% CI 1.60, 1.72) for total mortality. Accounting for competing risk of other causes of death, RA-ILD had an sdHR of 4.39 (95% CI 4.13, 4.67) for respiratory mortality and an sdHR of 1.56 (95% CI 1.43, 1.71) for cancer mortality compared with RA without ILD., Conclusions: RA-ILD was present or developed in nearly 5% of patients in this nationwide study of older patients with RA. Compared with RA without ILD, RA-ILD was associated with excess total, respiratory and cancer mortality that was not explained by measured factors., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose of Review: To summarize the current understanding of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) throughout the rheumatoid arthritis (RA) disease course from preclinical to established disease., Recent Findings: ILD is a serious extra-articular manifestation of RA. Multiple studies have demonstrated a high prevalence of both subclinical and clinical ILD throughout the RA disease course. Investigations of patients without RA have demonstrated an association between RA-related autoantibodies like anticitrullinated protein antibodies (ACPA) and interstitial abnormalities on lung imaging. A significant proportion of RA-ILD patients develop ILD prior to articular manifestations, suggesting that the lung plays a central role in RA development, perhaps through ACPA production. RA-ILD also occurs in early RA, when exuberant autoantibody production and systemic inflammation may propagate pulmonary disease activity. In patients with established RA, a high burden of subclinical and clinical ILD results in significant morbidity, mortality, and healthcare expenditure. Multiple epidemiologic and genetic risk factors, as well as serum biomarkers, have been associated with RA-ILD., Summary: Subclinical and clinical ILD occur frequently in preclinical, early, and established RA and may play a key role in RA-related autoantibody production and disease progression. Further studies are needed to better understand the risk factors, prognosis, and potential therapies for RA-ILD., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To determine the association between novel lifestyle factors on risk of rheumatoid arthritis (RA)-associated interstitial lung disease (ILD), define the threshold at which smoking increases RA-ILD risk, and calculate the degree to which known lifestyle and clinical factors predict RA-ILD., Methods: This nested case-control study matched incident RA-ILD cases to RA non-ILD controls on age, sex, RA duration, rheumatoid factor, and time from exposure assessment to RA-ILD. Exposures included education, BMI, smoking, anticyclic citrullinated peptide antibodies, race, joint erosions, rheumatoid nodules, C-reactive protein (CRP), disease activity score, functional status, disease-modifying antirheumatic drug use, and glucocorticoid use. OR for each exposure on risk of RA-ILD were obtained from logistic regression models. Area under the curve (AUC) was calculated based on all lifestyle and clinical exposures., Results: We identified 84 incident RA-ILD cases and 233 matched controls. After adjustment, obesity, high-positive CRP (≥ 10 mg/L), and poor functional status (multidimensional Health Assessment Questionnaire [MDHAQ] ≥ 1) were associated with increased risk of RA-ILD (OR 2.42, 95% CI 1.11-5.24 vs normal BMI; OR 2.61, 95% CI 1.21-5.64 vs CRP < 3 mg/L; OR 3.10, 95% CI 1.32-7.26 vs MDHAQ < 0.2). Smoking 30 pack-years or more was strongly associated with risk of RA-ILD compared to never smokers (OR 6.06, 95% CI 2.72-13.5). Together, lifestyle and clinical risk factors for RA-ILD had an AUC of 0.79 (95% CI 0.73-0.85)., Conclusion: Obesity, CRP, functional status, and extensive smoking may be novel risk factors for RA-ILD that may be useful for RA-ILD risk assessment and prevention. The overall ability to predict RA-ILD remains modest., (Copyright © 2021 by the Journal of Rheumatology.)

Background: Clinically evident interstitial lung disease (ILD) affects 10%-42% of RA patients with prognostic implications. The aim of this study was to discern which factors are associated with the presence of ILD in RA patients and to develop a score that could help to stratify the risk of having ILD in RA patients., Methods: Case-control study. We included RA patients recruited from ILD and rheumatology clinics. We retrieved the following data: gender, age, presence of extra articular manifestations, disease activity scores, antibodies status, ESR, and medication use. Multivariate logistic regression was performed. A risk indicator score was developed., Results: Of 118 patients included in this study, 52 (44%) had RA-ILD (cases) and 66 (56%) had RA without ILD (controls). Twenty-six patients were male (22%), the mean age was 56.6±15.6 years. Five variables were significantly associated with the presence of ILD: male gender, smoking, extraarticular manifestations, a CDAI score>28, and ESR>80mm/h. The AUC of the final model curve was 0.86 (95%CI 0.79-0.92). Two potential cut-off points of the risk indicator score were chosen: a value of 2 points showed a sensitivity of 90.38% and a specificity of 63.64%, while a value of 4 points showed a sensitivity of 51.9% and a specificity of 90.9%., Conclusion: This study identified risk factors that could help identify which RA patients are at risk of having ILD through the development of a risk indicator score. This score needs to be validated in an independent cohort., (Copyright © 2019 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.)

Background: Chronic tobacco smoke exposure results in a broad range of lung pathologies including emphysema, airway disease and parenchymal fibrosis as well as a multitude of extra-pulmonary comorbidities. Prior work using CT imaging has identified several clinically relevant subgroups of smoking related lung disease, but these investigations have generally lacked organ specific molecular correlates., Research Question: Can CT imaging be used to identify clinical phenotypes of smoking related lung disease that have specific bronchial epithelial gene expression patterns to better understand disease pathogenesis?, Study Design and Methods: Using K-means clustering, we clustered participants from the COPDGene study (n = 5,273) based on CT imaging characteristics and then evaluated their clinical phenotypes. These clusters were replicated in the Detection of Early Lung Cancer Among Military Personnel (DECAMP) cohort (n = 360), and were further characterized using bronchial epithelial gene expression., Results: Three clusters (preserved, interstitial predominant and emphysema predominant) were identified. Compared to the preserved cluster, the interstitial and emphysema clusters had worse lung function, exercise capacity and quality of life. In longitudinal follow-up, individuals from the emphysema group had greater declines in exercise capacity and lung function, more emphysema, more exacerbations, and higher mortality. Similarly, genes involved in inflammatory pathways (tumor necrosis factor-α, interferon-β) are more highly expressed in bronchial epithelial cells from individuals in the emphysema cluster, while genes associated with T-cell related biology are decreased in these samples. Samples from individuals in the interstitial cluster generally had intermediate levels of expression of these genes., Interpretation: Using quantitative CT imaging, we identified three groups of individuals in older ever-smokers that replicate in two cohorts. Airway gene expression differences between the three groups suggests increased levels of inflammation in the most severe clinical phenotype, possibly mediated by the tumor necrosis factor-α and interferon-β pathways., Clinical Trial Registration: COPDGene (NCT00608764), DECAMP-1 (NCT01785342), DECAMP-2 (NCT02504697)., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is one of the most serious extra-articular RA manifestations. RA-ILD is associated with worse physical function, lower quality of life, and increased mortality. RA-ILD is comprised of heterogeneous subtypes characterized by inflammation and fibrosis. Diagnosis can be difficult since the presentation of RA-ILD is characterized by non-specific symptoms and imaging findings. Management of RA-ILD is also challenging due to difficulty in precisely measuring pulmonary disease activity and response to treatment in patients who may also have articular inflammation. We provide a current overview of RA-ILD focusing on prevalence, risk factors, and treatment., Recent Findings: Research interest in RA-ILD has increased in recent years. Some studies suggest that RA-ILD prevalence may be increasing; this may be due to underlying biologic drivers or increases in imaging and recognition. Novel RA-ILD risk factors include the MUC5B promotor variant, articular disease activity, autoantibodies, and biomarkers of damaged pulmonary parenchyma. Treatment should focus on controlling RA disease activity, which emerging data suggest may reduce RA-ILD risk. Immunomodulatory and antifibrotic drugs may also treat RA-ILD., Summary: RA-ILD is an underrecognized and serious manifestation of RA, but important progress is being made in identifying risk factors and treatment.